Genomic variation at the MDR1 promoter and P-glycoprotein expression and activity in AML patients

Lourenço, Juliano Javert; Maia, Raquel Ciuvalschi; Scheiner, Marcos Antônio Maurício; Vasconcelos, Flavia da Cunha; Moreira, Miguel A. M.

doi:10.1016/j.leukres.2007.10.001

Cited by 9 publications

(6 citation statements)

References 16 publications

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“…Although our results on CC ! CT > TT in relation to Pgp function corroborate the data reported by others [13,[42][43][44][45], there are some discrepancies among authors, and the functionality of 3435 CT ABCB1 SNP remains a matter of controversy [7,[46][47][48][49][50]. In our renal transplant population, we described the influence of ABCB1 SNPs on Pgp function in PBMCs, supporting results reported in other tissues where the functional effect of Pgp polymorphism was also demonstrated [35,42].…”

Section: Discussionsupporting

confidence: 90%

Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study

et al. 2012

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SummaryThe function of the efflux pump P-glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was evaluated in PBMC using the Rhodamine 123 efflux assay. TT carrier patients on C3435T, G2677T, and C1236T SNPs (Pgp-low pumpers) showed lower Pgp activity than noncarriers. Pgp-high pumpers treated with cyclosporine showed lower values of Pgp function than macrolides. There was a negative correlation between cyclosporine AUC and Pgp activity at 3 months. Results did not show any correlation between tacrolimus and sirolimus AUC and Pgp activity at 3 months. We found an important role of the ABCB1 SNPs Pgp function in CD3 + peripheral blood lymphocytes from renal transplant recipients. Pgp activity was influenced by cyclosporine but not macrolides exposure.

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Section: Discussionsupporting

confidence: 90%

Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study

et al. 2012

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“…The putative transcription factor binding site predictor PROMO (ALGGEN Research Software http://alggen.lsi.upc.edu])[23,24] was used for in silico confirmation of reported cis-binding elements [15] and to predict potential transcription factor binding sites within the ABCB1 promoter region. A map of the proximal promoter sequence with the identified SNPs with known and predicted binding sites was generated (see Results).…”

Section: Methodsmentioning

confidence: 99%

“…Besides coding SNPs, other SNPs in the ABCB1 promoter could alter P-gp expression by affecting ABCB1 transcription. A few studies evaluated some of these SNPs individually but conflicting data were also reported [7,15–19].…”

Section: Introductionmentioning

confidence: 99%

Differential effect of ABCB1 haplotypes on promoter activity

Speidel

Abdel‐Rahman

2018

Pharmacogenetics and Genomics

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“…There are many SNPs in the ABCB1 promoter that could affect P-gp expression by affecting ABCB1 transcription. While a few studies evaluated the effect of some of these SNPs on ABCB1 expression, discrepant results were reported where the same SNPs were associated with increased and decreased expression and also with no effect (Ito et al, 2001; Lourenço et al, 2008; Sai et al, 2010, 2006; Takane et al, 2004; Tanabe et al, 2001). The lack of reproducibility between studies is not surprising because SNPs do not occur individually in the genome, but rather form defined combinations or haplotypes due to varying degrees of linkage disequilibrium between them.…”

Section: Introductionmentioning

confidence: 99%

Bisphenol A (BPA) and bisphenol S (BPS) alter the promoter activity of the ABCB1 gene encoding P-glycoprotein in the human placenta in a haplotype-dependent manner

Speidel

Abdel‐Rahman

2018

Toxicology and Applied Pharmacology

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Exposure to bisphenols (BPA and BPS) during pregnancy can significantly affect fetal development and increase risk of adverse health consequences, however the underlying mechanisms are not fully elucidated. In human placenta, the efflux transporter P-glycoprotein (P-gp), encoded by the ABCB1 gene, extrudes its substrates from the trophoblasts back into the maternal circulation. Alterations in levels of placental P-gp could therefore significantly affect fetal exposure to xenobiotics that are P-gp substrates. The ABCB1 promoter contains many single nucleotide polymorphisms (SNPs). In the genome, SNPs are not arrayed as independent variants but as combinations forming defined haplotypes. Recently, we determined the haplotype sequences encompassing the ABCB1 promoter SNPs and found that promoter haplotypes differentially affect ABCB1 promoter activity. Here we investigate the effect of BPA and BPS on ABCB1 promoter activity by testing the hypothesis that BPA and BPS exposure affect ABCB1 promoter activity in a haplotype-dependent manner. Our data indicate that acute exposure to 50 nM BPA induced a significant haplotype-dependent increase in ABCB1 promoter activity (P < .05). However, acute exposure to 0.5 nM BPS induced a significant decrease (P < .05) in promoter activity that was haplotype-dependent. Chronic exposure to BPA and BPS individually (5 nM and 0.3 nM, respectively) or as a mixture (5 nM BPA:1.5 nM BPS) induced significant haplotype-dependent increases (P < .01) in ABCB1 promoter activity. Our data indicate that BPA and BPS significantly alter ABCB1 promoter activity in a haplotype- and exposure type- dependent manners. Such alteration could significantly impact placental P-gp levels and alter fetal exposure to many therapeutic and environmental xenobiotics.

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Genomic variation at the MDR1 promoter and P-glycoprotein expression and activity in AML patients

Cited by 9 publications

References 16 publications

Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study

Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study

Differential effect of ABCB1 haplotypes on promoter activity

Bisphenol A (BPA) and bisphenol S (BPS) alter the promoter activity of the ABCB1 gene encoding P-glycoprotein in the human placenta in a haplotype-dependent manner

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